a. Field of the Invention
This invention relates to an antibiotic, a new composition of matter called AY24,668, and to a process for its preparation. AY24,668 is useful as an antifungal agent.
b. Description of the Prior Art
The antibiotic of this invention is readily distinguished from prior art compounds of its class by its profound antifungal activity and its relatively low order to toxicity.
More explicitly, the ultra violet spectrum of AY24,668, noted herein, indicates that this compound belongs to the class of antibiotics known as triene antibiotics. In this particular class there are only six compounds reported previously. Trienine, A. Aszalos et al., J. Antibiotics, 21,611 (1968) is a triene antibiotic with antitumor activity which also shows marked activity against gram positive organisms and only marginal activity against Candida strains. The antifungal triene reported by J. J. Armstrong, et al., Nature, 206, 399 (1965) and Mycotrienin reported by C. Coronelli et al., J. Antibiotics, 20, 329 (1967), representing the second and third antibiotic, are probably identical. Both have low antifungal activity (MIC against Candida Albicans: 5 .mu.g/ml) and high toxicity (LD.sub.50 in mice: 15 mg/kg). The fourth and fifth antibiotics-Resistaphylin, S. Aezaiva et al., J. Antibiotics, 24, 393 (1971) and Proticin, G. Nesemann et al., Naturwissenschaften, 59, 81 (1972) are readily distinguished from the compound of the present invention in that they exhibit antibacterial without any antifungal activity.
The sixth triene is antifungal rapamycin which is distinctly different from AY24,668 as indicated by comparison of their NMR spectra. Both may be structuraly related. Rapamycin is an antifungal antibiotic described by C. Vezina et al., J. Antibiot., 28, 721 (1975), S. N. Sehgal et al., J. Antibiot., 28, 727 (1975), S. N. Sehgal et al., U.S. Pat. No. 3,929,992, issued Dec. 30, 1975 and S. N. Sehgal et al., U.S. Pat. No. 3,993,749, issued Nov. 23, 1976. The latter two patents are herein incorporated by reference. Rapamycin is extracted from a streptomycete (Streptomyces hygroscopicus) isolated from an Easter Island soil sample and is particularly effective against Candida albicans both in vitro and in vivo, H. A. Baker et al., J. Antibiot., 31, 539 (1978).
Although AY24,668 is produced by the same microorganism as rapamycin, AY24,668 lacks the immunosuppressant activity of rapamycin [R. R. Martel et al., Can. J. Physiol., 55, 48 (1977)], and, therefore, is better suited for use as an antifungal agent.